Copyright � 2008 by the Genetics Society of America

Perspectives

Anecdotal, Historical and Critical Commentaries on Genetics

Edited by James F. Crow and William F. Dove

Robert L. Metzenberg, June 11, 1930–July 15, 2007: GeneticistExtraordinaire and ‘‘Model Human’’

Eric U. Selker1

Institute of Molecular Biology, University of Oregon, Eugene, Oregon 97403-1229

The genetics world was saddened by the recent death ofBob Metzenberg. We invited Eric Selker to write aninformal biography and tribute and several others towrite remembrances. These illustrate the high esteem inwhich he was held by his colleagues. Among other honors,Bob was elected to the National Academy of Sciences andin 2005 was awarded the Thomas Hunt Morgan Medal bythe Genetics Society of America.

J. F. Crow and W. F. Dove

I first met Bob Metzenberg (Figure 1) when he cameto Reed College to give the Gabriel Lester Memorial

Lecture in 1974. He made a convincing case for usingthe fungus Neurospora crassa to investigate gene regulationin eukaryotes. This was, of course, before DNA-mediatedtransformation of Neurospora and other eukaryotes,before the invention of recombinant DNA techniques,and even before a reliable method of extracting nucleicacids from Neurospora had been described. However, asanyone who has heard Bob give a presentation, formallyor informally, knows, he had a knack for arranginginformation into tight stories and his special blend ofhumor and style ensured that even potentially sleepyundergraduates remained tuned in. Bob described hisinvestigations on regulation of sulfur and phosphorusutilization at a time when little was understood aboutgene regulation in eukaryotes. His identification of mul-tiple regulatory mutants and his demonstration that theunderlying genes exist in a hierarchy to turn on familiesof unlinked structural genes was clearly a major advance.Indeed, Bob was the first to discover a cascade of positive-and negative-acting products of regulatory genes actingto govern eukaryotic gene expression. These studies fore-shadowed the discovery of similar signal transductionsystems in other organisms. Bob Metzenberg was not aperson who tooted his own horn, however. ½For example,he was not the type who ‘‘casually’’ mentioned that hewas a member of the National Academy of Sciences, wasawarded a MERIT grant, and had one of the longest-

running National Institutes of Health grants ever (over38 years) or that he had been awarded a slew of otherprestigious honors, including the Thomas Hunt MorganMedal (Selker et al. 2005).�

Visiting the Metzenberg laboratory 4 years later leftme with two other strong impressions of Bob: hisapproachability and the breadth and depth of his in-tellectual tool chest. I discovered that he was a chemistdisguised as a geneticist. The disguise was effective be-cause he was an extraordinary geneticist, but his core ofchemistry served him well: as an award-winning bio-chemistry professor, as a molecular biologist, and as anadvisor for thousands of students and colleagues wholearned to seek his advice. Those who interacted withBob quickly discovered that the value of his extensiveknowledge base was amplified by his uncommon imag-ination and by his legendary generosity. Gerry Finkrecently noted,

Bob was a wonderful scientist and intellectually adventur-ous person. He had a remarkable grasp of metabolism andits integration into the physiology of an organism. Fromthe time I began an independent career, Bob was myresource for any baffling interaction that I couldn’t makeheads or tails of. On one occasion I mentioned a peculiargrowth behavior of a mutant in the glyoxalate pathway.Bob always greeted such puzzles with an affectionatebroad grin. This was the kind of problem that tickled hisfancy, even though it was my problem. Without hesitation,he made a key connection between glyoxalate metabolismand gluconeogenesis that had completely eluded my stu-dents and me. The connection he made formed the basisfor many important discoveries in my laboratory. Like somany of his colleagues, I found my career influenced byBob’s unique scientific style and generous spirit.

‘‘DEFINING CORE,’’ EDUCATION, AND CAREER

Robert Metzenberg was born on June 11, 1930, inChicago, where his great-grandfather had settled.Apparently Bob’s great-great-great-grandfather, the1Author e-mail: selker@uoregon.edu

Genetics 178: 611–619 (February 2008)

‘‘Stammvater,’’ or first Metzenberg with a surname, wasa fairly successful furrier, dyer, and leather worker inGermany. Bob owed his life to the fact that one of hisgreat-great-great-grandfather’s sons decided to stay inIreland after going there to buy a supply of leather. AfterI told Bob about visiting Germany to participate in a tri-bute to relatives of mine lost in the Holocaust, he wrote tome that he had tried to trace relatives who had lived on theContinent but his research invariably led to ‘‘in Buchenwaldgestorben’’ (died in Buchenwald). He concluded,

It seems that nobody in my patronymic family survived theHolocaust. I have no living relative on the Continent onmy mother’s side either. . . . The Holocaust was muchtalked about in my family when I was a small child. I haveno doubt that horror of it was, and is, the defining core ofmy life. I have never lost my gratitude for having been bornin this country, nor have I ever taken my luck for granted.

From an early age Bob lived intensely and made themost of life. Growing up, he focused on competitiveswimming, photography, and baseball and excelled in

arithmetic and spelling at the expense of English andart. He earned spending money mowing lawns, whichfinanced movies, dates, etc. He cared about the worldand idolized Adlai Stevenson. After graduating fromhigh school, Bob headed west to Pomona College andmade firm ties in California.

At Pomona, Bob majored in chemistry and minoredin physics and biology, which he noted were ‘‘almostimmiscible with chemistry’’ at the time. His Pomona andlife-long buddy George Becker reflected,

The Chemistry Department was anything but stuffy. Prof.R. Nelson Smith and his partner Corwin Hansch wereconstantly pranking one another and set the tone fortheir students. Partly as a result of his own DNA andcertainly as a result of being in that Chemistry Depart-ment, ‘‘Metz’’ was emboldened to pull pranks constantly.No one enjoyed it more.

Becker also noted,

Metz was bright, very bright and used to astonish hisfriends by ‘‘testing out’’ of classes. He seemed to be able to

Figure 1.—Bob Metzenberg. Bob loved thinking about science in his free time. The handwriting in the background is fromletters written by him while waiting for planes. In one he suggested a possible way to recognize N-methyl adenine in conjunctionwith the Church–Gilbert genomic sequencing method. The two additional people in the bottom image are Joan Bennett andDavid Perkins.

612 E. U. Selker

avoid taking beginning classes and in doing so he was veryself denigrating saying he was ‘‘lucky’’ etc.

In 1951 Bob graduated Phi Beta Kappa and enrolledin the Division of Biological Sciences at the CaliforniaInstitute of Technology for graduate studies. He workedwith Herschel Mitchell on the synthesis of certain aminoacids and interacted with an impressive group of ge-neticists and biochemists, including George Beadle, EdLewis, A. H. Sturtevant, and Max Delbruck. Matt Mesel-son commented, ‘‘Bob greatly helped to make CalTechthe humane and intellectually exciting place it was inthose days.’’

Bob did manage to find time for necessary fun,however. For example, Bob Lester recalls ‘‘many finememories of extracurricular hijinks while we were stillbachelors, e.g., skinny dipping on a hot deserted beachin Mexico with Bob and Len Hertzenberg and payingfor the sunburn where the sun doesn’t usually shine.’’

While at CalTech, Bob married Helene Fox of Pasa-dena, and afterwards they moved to Madison, Wisconsin,so that he could do postdoctoral research in the De-partment of Physiological Chemistry at the University ofWisconsin School of Medicine. Bob worked with PhilipCohen on enzymatic reactions involved in urea synthesisin mammals and amphibians, but he became increas-ingly interested in the underlying gene regulation. Hetherefore took a 1-year visiting scientist position in thegroup of Ernst Hadorn in Zurich to do some ‘‘readingand listening’’ and to get ‘‘hands-on experience in de-velopmental genetics.’’ In 1958 Bob returned to theDepartment of Physiological Chemistry as an assistantprofessor and decided to study the regulation of enzymesynthesis in a simple eukaryote. He chose Neurospora,with which he had become familiar as a graduate stu-dent. He wanted to answer such questions as: (1) Howmany genes are involved in the regulation of typicalfamilies of adaptive enzymes?, (2) Do these genes act bypreventing the activity of spontaneously active genes orby engendering the activity of otherwise inactive genes?,(3) If several genes are involved in the regulation ofsuch pathways, do they exist as parallel, alternative sig-naling mechanisms or as a hierarchical series?, and (4)Do the structural and regulatory genes involved in afamily of adaptive enzymes tend to map close togetheror are they scattered throughout the genome? In a tourde force, in the 1970s Bob and his colleagues answeredall of these questions for genes required during depri-vation of phosphorus or sulfur.

In 1977 Bob visited Stanford, where I was a graduatestudent, and we exchanged notes about our respectiveefforts to clone interesting Neurospora genes. After Iextolled the virtues of building genomic libraries inphage rather than in plasmids, Bob invited me to visit hislab to help them set up some things. My visit, in May1978, was pivotal for me, leading to decades of enjoyablecollaborations and enduring friendships. Although

neither of us had been successful in isolating the genesin which we were most interested, we tried to make thebest of those that came relatively easily, such as rDNAgenes. A joint ‘‘side project,’’ to characterize the 5S rRNAgenes of Neurospora, became central to both of our ef-forts (Selker et al. 1981). We exchanged countless let-ters and phone calls on everything from technical detailsto potential mechanisms of concerted evolution ofdispersed genes. Bob’s colorful writing livened up evenmundane topics. Here are a few snippets from a rep-resentative letter of 1981:

That should be impossible, I think, because there shouldbe no RI site with lambda sequences on both sides of it.I’m trying again, and hope nothing so interestinghappens next time.

. . .

Well, that’s all woolgathering at this point, but theexperiments to be done are fairly obvious. Or at leastsome of them are. Give me your thoughts on this too!

. . .

Everything seems to violate common sense, but perhaps afew solid facts will shape it up.

. . .

I couldn’t help thinking of something wild: parsley is oneof those plants, along with (at least) celery and parsnips,that contain psoralens at quite substantial concen-trations. . . . It would certainly be interesting if the genein a living plant ever turned into snapback DNA inresponse to infection or injury, but I admit it’s a crazyidea.

Two years later, when I joined Bob’s lab after a stint inGermany, I found him still working on the 5S genes. Inan application for a Guggenheim Fellowship (awardedfor his sabbatical in 1983), Bob commented, ‘‘In thelast couple of years, accidental events have sparked myinterest in a biological problem on which I had notpreviously done any research.’’ To map the 5S RNAgenes, Bob developed RFLP mapping for Neurospora(Metzenberg et al. 1984, 1985). In reference to this,Wayne Versaw, Bob’s last graduate student wrote,

During a conversation in 2000, I asked Bob which sci-entific accomplishment he was most proud of in hiscareer. His answer, without even a slight hesitation, wasthe use of RFLPs for genetic mapping. Although RayWhite and David Botstein described the use of RFLPs first(1980), Bob had independently worked out the conceptof using naturally occurring polymorphisms for geneticmapping and his group published in 1984 an extensiveRFLP map of Neurospora crassa and a detailed protocolthat is still used to this day. I was struck by the fact thatone of his most prized accomplishments was strictlypersonal—no glory or credit, just the satisfaction of doinggood science.

In the late 1980s and early 1990s, Bob and members ofhis laboratory made important contributions in otherareas, including characterizing the structure and func-

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tion of mating genes of Neurospora (Glass et al. 1988,1990a,b; Metzenberg 1990; Metzenberg and Glass

1990; Nelson and Metzenberg 1992; Randall andMetzenberg 1995; Ferreira et al. 1998), discoveringa premeiotic process resulting in drastic changes inthe number of tandem rDNA repeats in the genome(Butler and Metzenberg 1989) and isolating andcharacterizing the phosphorus family genes (Mann

et al. 1988; Kang and Metzenberg 1993; Peleg et al.1996) that Bob had identified genetically in the early1970s (for review, see Metzenberg 1979). He alsocontinued to design and share imaginative technicaladvances, such as a method to use ‘‘sheltered RIP’’(repeat-induced point mutation) to identify and studyessential genes (Harkness et al. 1994) and a newchemical method to couple DNA to glass slides formicroarray experiments (Dolan et al. 2001). Mary Casenoted,

Bob had an overall knowledge of Neurospora. He wasinterested in the whole organism from new methodsto isolate tetrads, new mapping procedures, biochemi-cal genetics, molecular biology and new techniquesin working with DNA. He was a frequent contributorwith his ideas to the Neurospora Newsletter and laterto the Fungal Genetics Newsletter. His ideas were al-ways useful and unique. He was a wonderful person totalk to you about your research. He always had goodquestions and ways to help you achieve the results youwanted. . . .

Bob’s generosity and creativity together yielded count-less contributions to the community. A typical multi-pageletter from Bob in 1991, describing a new idea for iden-tifying recessive mutations in essential genes, startedwith, ‘‘I have no special reason to think you need this

procedure, but I wanted to give you, Mary Anne andLouise copies of this in case it proves useful.’’

Immediately before ‘‘retiring’’ in 1996, Bob and hispostdoctoral fellow discovered a remarkable and un-expected new epigenetic phenomenon in Neuros-pora, initially called meiotic transvection and laterrenamed ‘‘MSUD’’ for meiotic silencing by unpairedDNA (Aramayo and Metzenberg 1996; Shiu et al. 2001).Elegant work, largely devised and carried out by Bobindependently, showed that any sequence that is un-paired during meiosis elicits an RNAi-like mechanismthat silences all homologous sequences in the genome,paired or unpaired, for the duration of meiosis. Thefinding that MSUD is mechanistically related to RNAicame from one of Bob’s characteristically imaginativegenetic schemes for selecting suppressor mutations.

As detailed below in the remembrance by NambooriB. Raju and David J. Jacobson, while fighting cancer,Bob worked his last 10 years as an emeritus professor,first at Stanford, followed by UCLA, California StateUniversity at Northridge, and, finally, up until his finalday, in his home laboratory (see Figure 2).

In his marvelous style, in January of 2007, Bob wrote apiece entitled ‘‘Research in your retirement house’’ (p. 7of http://www.genetics-gsa.org/pdf/newsletter_jan07.pdf), which starts out:

Retirement can be one of the most productive andsatisfying times of your scientific career. All you need isa spare, dedicated room, an understanding and patientcompanion, neighbors who don’t suspect you of brewingup anthrax bacilli, and a small amount of money.

He goes on, suggesting,‘‘do not be shy about doing abit of dumpster-diving at an institution near you’’ and

Figure 2.—Bob and his home laboratory.Clockwise from top left: Bob, January 2007;‘‘stockroom’’; microscope and work table; ‘‘auto-clave.’’

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notes that ‘‘younger people will see you as a harmlesseccentric.’’ He then proceeds to explain that whennormal job constraints are suddenly removed, ‘‘onediscovers how severely they limit our ability to follow uphigh-risk, high-payoff ideas.’’

STYLE AND HUMOR

Bob’s enjoyable and interesting style was not onlyevident in his writing and speaking—it came through inall aspects of his life. He made the extra effort to addflair, consistent with his entry in a ‘‘Grandfather Re-members’’ book that he filled out when his granddaugh-ter was born in 1985. He said that a simple statementthat sums up his attitude about life is: ‘‘it should beenjoyed and lived with a little enthusiasm and flair. Weshould be ready to leave when it’s over.’’

Clearly, Bob had no shortage of ‘‘enthusiasm andflair.’’ Craig Wilson, who was curator of the FungalGenetics Stock Center, contributed the following from atypical Metzenberg postcard:

I apologize for calling you Doctor, and didn’t know whetherit applied or not. When people ask me if I like to be calledDr. or what, I tell them my real preference would be to becalled ‘‘Oh, Venerable One,’’ but too often it comes out‘‘Venereal One.’’ My second favorite name is ‘‘Bob.’’

Probably everyone who interacted with Bob has atleast one example of his humor coupled with his hu-mility. I selected the following examples from e-mailsthat Bob sent me over the last few years, written whilealready fighting for his life:

Thank you for your kind words. I still think they made aclerical error and some poor secretary is going to be fired.

. . .

Sorry it’s taken me several days to answer your letter. Mymind seemed to be going ta-pocketa on one cylinder, butthis morning a second cylinder seems to be coughingfitfully into action. Let me try to state the problem to see ifI have got it right.

. . .

Some or all of you may tell me I have devised theNeurospora equivalent of an appendix transplant. I awaityour criticisms! Alternatively, would anybody be willing topick a few interesting, obviously essential genes and try aproof-of-principle? I would try to be helpful.

. . .

I finally clicked into Genetics, and, lo and behold, there Iwas. At last I understand how a ‘‘woman of a certain age’’feels when she gets an extreme makeover at a top-of-the-line spa and likes the stranger she sees in the mirror. Ihaven’t forgotten that, despite your kind profile, I’m stillme, warts and all. Nevertheless, it was more than generousof you to airbrush them out.

. . .

As far as I am concerned, fruitcakes are one of thecrowning achievements of Western civilization, and will

persist after the Sistine Chapel has crumbled into ruinsand the late Beethoven Quartets have been forgotten.Well, almost, anyway.

. . .

With a little luck, I will be around for a long time tobedevil my friends and family, but if that’s not in the cards,I want things to be left reasonably shipshape.

. . .

I’m sorry it took me five days to respond to your letter. Itwas my druggy week, and I have been sleeping most ofevery day and spending my waking hours wandering on astrange, cratered planet on which I am the only life form.Finally yesterday I started to return to earth, and today Ieven drove into UCLA and got some samples ready forPatrick to work on tomorrow. The next two weeks will befine—then it all starts over again, unfortunately. I shouldcount my blessings: hardly anyone has it so easy.

. . .

Thank you so much for the letter, which is full ofinteresting ideas that I want to study further. It cheeredme up to be hearing and thinking science again!

. . .

You were correct in guessing that I might be full ofpoisons that would keep me from responding promptly oreven lucidly. It has been a less than perfect month, whichfinally culminated in a substantial stay in the hospital witha pulmonary embolism. Since I have only three of myoriginal five lobes, losing function in one of them was veryunwelcome. I am, thank goodness, now discharged fromthe hospital. However, no more bungee-jumping, sky-diving, or street-fighting allowed; I will be on blood-thinners from here on out.

After nearly succumbing to pneumonia in January2006, Bob wrote,

. . . a few people have told me from time to time that Ihave walked the earth with no baggage, and that I am acompletely uncomplicated person. I wish it were true, butthe right moment to correct this impression has neverpresented itself. But after I go to that Big Lab Bench in theSky, someone may say so again. I don’t want to have mycharacter prettied up any more than my physical remains.I’ve elected you to say ‘‘It ain’t so!’’

The fact is that Bob’s character and credentials arenot at all in need of being ‘‘prettied up’’: they areimpressive in their native state. Bob was a modelscientist, continuously doing research with his ownhands and overflowing with ideas, energy, and flair. Hewas a natural tinkerer and educator who also inspiredothers to try ‘‘wild’’ things. Moreover, he was a modelhuman being: caring and generous with a great sense ofhumor. And in spite of his talents, Bob was exceptionallymodest. He was complex, but only in a positive way. Wewill continue to miss him tremendously.

REMEMBRANCES FROM THE WISCONSIN COMMUNITY

The following remembrances are from colleagues atthe University of Wisconsin, where Bob Metzenberg

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joined the faculty in 1958 as an assistant professor ofphysiological chemistry. Bob’s role on the faculty of thatdepartment in the medical school is expressed by hiscolleague Larry Kahan:

When I joined the Physiological Chemistry Depart-ment in 1973, I was given the opportunity of sitting in onBob’s lectures to the medical students. I did this withmore than a little interest since I was slated to take oversome of those lectures the following year. I was surprisedand impressed by the way in which Bob could take asrelatively dry a subject as the biochemistry of bloodclotting and weave in everything from European historyto the similarities between genetic dissection of apathway and biochemical dissection of a pathway inways that captured the interest of the medical students.His lectures had everything—basic biochemical andgenetic principles, clinical examples, and a good deal ofvery dry humor. Bob made it clear to the students that hewas not just teaching them biochemical facts: he was alsopreparing them to understand and incorporate thebiochemistry that they would encounter in the severaldecades of their careers as physicians.

Behind the scenes I had some long discussions aboutteaching philosophy with Bob. At the time, the medicalschool was starting up a new, independent study cur-riculum. Bob had some very definite ideas about teach-ing, particularly about the value of integrating the basicscience courses of the first semester by studying the sub-jects concurrently rather than serially, the unique learn-ing gained from hands-on laboratory experiences, thevalue of the lecture as a teaching method, and the properway to test students, which were at odds with the then-current philosophy of the medical school. He was instru-mental in arriving at a compromise that maintained someof these elements even in the new independent studycurriculum (eventually abandoned several years later).

Bob was truly a dedicated teacher. He loved being inthe laboratory with students during the enzyme kineticslaboratory, walking around and pointing out that theycould see the tubes changing color as the reaction pro-ceeded. His lectures were classics. When introducingthe subject of prenatal diagnosis, Bob began with thefollowing:

‘‘A Whimsical Example Illustrating the Principle.’’ I havechosen prenatal diagnosis of Transylvanian Vampirism toemphasize that we don’t need to know the relationbetween the gene and phenotype to apply this method.The analysis is made possible by linkage of the genegoverning this trait to the gene which determines roundvs. square toenails. Vampirism is caused by homozygosisfor the recessive allele, vp (genetic constitution vp/vp).Heterozygotes and homozygotes (Vp/vp and Vp/Vp, re-spectively) are not vampires. In the romance of thecentury, Melanie Moozendoodle and Gary Gazinkuscourted, wed, and started procreating. Unbeknownst tothem they were both descendants of the infamous VladTepes the Impaler (Count Dracula) and were hetero-zygotes of constitution Vp/vp. This came to light when

their firstborn turned out to be a vampire. . . . WhenMelanie became pregnant again, she decided that nurs-ing one child from her jugular vein was enough. Gary,who was taking half the night feedings, agreed. Yet theyknew that there was one chance in four the fetus she wascarrying would be a homozygote, like its older sibling. Thehollow saber incisors characteristic of vp/vp homozygotesappear only at birth, so there is no way this can be directlyobserved in the fetus. Can any predictions be made?

Bob then proceeded by analysis of linkage of thevampirism gene to the toenail-shape gene to theconclusion that:

The new Gazinkus child is the joy of her parents’ lives.The only sign of her heterozygous condition is that, likethe parents themselves, she gets a craving for bloodsausage when the moon is full.

After capturing the students’ interest, Bob then wenton to introduce the students to prenatal diagnosisthrough the use of closely linked RFLPs.

Bob’s knowledge was truly encyclopedic. It was wellknown and appreciated that if you had a really strangequestion you could not answer that Bob was the personto ask, no matter how unrelated the question might beto his teaching or research. I took frequent advantage ofthis, and he never disappointed. He was always willing totake on extra teaching to help out a colleague, some-times giving a lecture literally on a moment’s notice.

Finally, Bob really cared about the students. He waswilling to spend hours going over the material withstudents who were having difficulty. He delighted inworking with students who wanted to extend thematerial that he had covered.

Within the mega-university of Wisconsin, as in many aresearch university, a faculty member could fully occupyhimself with his research program and his departmentalresponsibilities. Not so, Bob Metzenberg, as explainedin the following by Bill Dove:

Bob and I first came together as pioneers. Workingwith Walter Plaut (zoology) and Millard Susman (ge-netics), we (physiological chemistry and cancer biology)crossed the college and departmental matrix of themega-university that is Wisconsin. We were driven onlyby our shared enthusiasm for the emergent fields ofmolecular genetics and molecular cell biology and byour enjoyment of the spectrum of undergraduates inthis land-grant university who chose to join us to explorenew fields of inquiry without boundaries. Our guidingeducational principle was the importance of ‘‘TheExperiment.’’ For a full year, we four designed a set ofnovel experiments in cell biology, biochemistry, andgenetics. For decades afterward, Bob continued to de-sign experiments for Biocore as it grew from a cottageindustry to one of the bulwarks of undergraduate edu-cation in biology at Wisconsin. Indeed, The Experimentwas Bob’s lifeblood—for his own science and then forhis teaching of others.

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Another example of Bob’s talent for explanation ofseemingly subtle ideas is offered here by Millard

Susman:

In the Biocore course, Bob wanted to make the point thatthe various scientific disciplines were distinguished by themethods that they used and by the kinds of questions thatthey asked. He told the students that a biochemist whowanted to understand a motor car would grind it up,reducing it to a pile of little chunks, and then wouldseparate the chunks from one another, studying eachchunk separately to try to figure out what it did and how itdid it. An anatomist would get a huge band saw and slicethe car like a salami. The anatomist would then study theslices individually and in sequence to try to figure out thecontours of the individual parts and to determine whichparts were connected to one another and how they areconnected. A geneticist would work with the whole car,removing one bit at a time—a valve here, a gear there—-and see how the removal of that one part affected theoperation of the car. It was an immediately comprehen-sible and memorable analogy.

Bob’s life at Wisconsin, in the university and in thecommunity, knew no boundaries. During the threedecades following our foray into the wilderness ofBiocore, many of our encounters involved mutuallyenjoyed musical events. Bob had a finely tuned sensitiv-ity to the differences among people—beyond thestudent body at Wisconsin. We would often exchangepostcards from new travel discoveries. We and our wivesjointly came forward to help preserve Wisconsin’sclassical American Player’s Theater (APT), where Bobagain demonstrated his ability to cross disciplines.Discovering with Louise Glass and others that thedifferent alleles of the highly polymorphic mating-type loci of fungi each arose from a distinct sequenceorigin, Bob consulted with the classics professor ofBeloit College who was directing one of the plays atAPT. From that consultation was born the neologism‘‘idiomorph.’’

Bob Metzenberg’s quick sense of humor was en-hanced by his ability to recall facts and events thatallowed him to view events in unusual ways. Both withinand outside of the laboratory and classroom he was wellknown for his encyclopedic knowledge of tastes andsmells. Jim Dahlberg has noted how these latter abilitiesmade him a very popular expert at wine-tasting gather-ings. He was said to have a ‘‘gas-chromatographic nose’’for ketones and esters. He was a cofounder and an activemember of a tasting group that still meets regularly, andhis wry comments kept the group from becoming tooserious about itself.

The decade in California, described below, generatedthe end of this story. We continued to exchange mes-sages about new ideas, and in 2005 Bob stepped for-ward to write a masterly essay on one of his Caltechmentors, Norman Horowitz, for the Perspectives article inGenetics (Metzenberg 2005). Our last encounter wasin January 2006 when Alexandra and I briefly visitedBob and Helene in Northridge. Again, The Experiment

took first place. Bob announced that he was publishingwith Patrick Shiu and others a study on the perinuclearlocalization of the RNA-directed RNA polymerase in-volved in meiosis in silencing the expression of unpairedgenomic sequences (Shiu et al. 2006). This article wasimportant enough to elicit a ‘‘Comment’’ (Kelly 2006).‘‘I chose to submit this to the Proceedings by Track II,’’said Bob, eschewing the option of coordinating its reviewhimself as an Academy member. This message was cutfrom the same cloth as the final word of Bob’s tribute toHorowitz (Metzenberg 2005, p. 1448):

Somehow, Norm always managed to tell the truth withoutbecoming a scold. There can never be enough of suchpeople, and his legacy must be kept alive.

Operating outside the traditional academic bor-ders, enriching the scientific communities of Caltech,Wisconsin, Stanford, and Neurospora, engaging dis-ciplines beyond science, Bob Metzenberg created aremarkable life from three elements: experiment, com-munication, and truth.

REMEMBRANCES FROM THE CALIFORNIA COMMUNITY

Rowland Davis (University of California at Irvine):

I met Bob in 1961 at the very first NeurosporaInformation Conference in La Jolla, California. Themeeting was free for all, in both senses of the phrase,and Bob and I began talking at the free bar after the last-night banquet. Characteristically, he drank Coke, and Idrank Canadian Club. Even as I became less articulate,he became more so, and I remember only one thingfrom that night: I had made one of the best scientificfriends of my life.

Bob was then at Wisconsin. I had taken a job at theUniversity of Michigan. I kept seeing Bob at meetings, andin the early 1970s, our labs exchanged visits. In Ann Arbor,Bob inspired one of my most daring experiments—one I had thought impossible if he had not said, ‘‘Whynot?’’ At that point, almost whimsically, he rattled off aprotocol that might do the job, and within a month weaccomplished the task. This was his habit: using hismulti-tasking imagination to explore, at the speed oflight, landscapes of possibilities in ways that Mozartmight have used to choose harmony and orchestration.As we, his friends, coupled our imaginations to his, wefelt that even his hypothetical dead ends were moreilluminating than a close scrutiny of quantitative data.He proved repeatedly Francis Bacon’s point that thetruth is better served by error than by confusion. Heremains a model of how much sheer fun science—andtalking about science—could be.

Out of context, one of his remarks about himselfmight sound ridiculous: ‘‘I had no talent!’’ But thecontext is illuminating. Having taken instruction inmusical composition earlier in life, he had completedseveral string quartets. He related this to me over lunch

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one day at Stanford, saying, ‘‘They were competent, butthey simply followed the rules. Derivative of Haydn andall. But I discovered I simply had no talent!’’ Thisillustrates not only Bob’s aesthetic refinement, but alsohis curious blend of modesty and ambition, an ambitionto use his mind to the fullest. It also explains hissymphonic understanding of the complex biochemicalsystems that he probed with a sensitivity to detail, subtlecomplexity, and the surprising formal beauty of cascaderegulatory systems.

Finally, Bob became one of the best friends of all of usin our scientific community. Always good humored andanxious to help, he willingly suffered fools, hoping atfirst that he might show them the light. A lack of successwould then bring out advice in an advanced play onwords that at least he could enjoy. Finally, the foolswould retire, yielding Bob’s attention to others betterequipped to enjoy it. I believe Bob made few enemies,largely because he retained a reserve that few people—myself included—fully penetrated. But what overlaythat reserve amounted to an incomparable friend andscientist, one who will glow in the dark for years to come.

Namboori B. Raju and David J. Jacobson (StanfordUniversity) interacted with Bob after he retired fromWisconsin and provided the following comments on histime in California:

Bob Metzenberg was no stranger to California; he washere first as a student and later as a retiree. When Bobretired from the University of Wisconsin in 1996, hereturned to California to be closer to his family. Histwo sons live in California: Howard in San Franciscoand Stan in Northridge near Los Angeles. Bob choseStanford for continuing his Neurospora research,mainly because of David Perkins and Charley Yanofskyin the Department of Biological Sciences. This was Bob’ssecond sojourn at Stanford, the first being a 6-monthsabbatical in the Perkins laboratory in 1983. Bob’s re-search interests had long overlapped with those of thePerkins lab, especially in the areas of Neurospora sexualbiology (Metzenberg 1995), mating-type genes, rRNAgenes, and, more recently, meiotic silencing (Shiu et al.2001). He was at ease with classical genetics as well as withmolecular biology, and he practiced both at Stanford. Inearly collaborations, Bob provided molecular data for theanalysis of a chromosome rearrangement, which has abreakpoint in the nucleolus organizer region that is com-posed of 150–200 rDNA repeats (Perkins et al. 1986).

In January 1996, Bob and his postdoc RodolfoAramayo settled into the Perkins lab. Here, Bob contin-ued his seminal research on a new phenomenon firstcalled transvection, and since renamed meiotic silencingby unpaired DNA (MSUD) (Aramayo and Metzenberg

1996; Shiu et al. 2001). After Rodolfo left for a facultyposition at Texas A&M in 1997, Bob, together withPatrick Shiu, Namboori Raju, and Denise Zickler inFrance, greatly extended meiotic silencing studies by

ectopically inserting single genes (at the his-3 locus),whose function is essential for meiotic progression.When such strains are crossed with wild type, the un-paired DNA sequences trigger RNAi-mediated silencingprocesses involving the RNA-directed RNA polymerasesand dicers, in addition to several other components.Consequently, ascus development is abnormal in het-erozygous crosses because of meiotic silencing of un-paired genes, but their development is completelynormal in homozygous crosses. Bob isolated two sup-pressor mutants of meiotic silencing, Sad-1 and Sad-2,whose wild-type gene functions are essential for meioticsilencing (Shiu et al. 2001, 2006; Shiu and Metzenberg

2002). The availability of GFP-tagged histone H1 andb-tubulin genes greatly facilitated the visual demonstra-tion of meiotic silencing and its suppression duringascus development (Freitag et al. 2004; Raju et al. 2007;Jacobson et al. 2008). Shiu and Raju had the privilegeof collaborating with Bob on several of these researchprojects. The last of five joint articles with Raju waspublished in May 2007, barely 2 months before Bobpassed away (Raju et al. 2007). Bob was extremelypleased that the article was among the ‘‘Issue High-lights’’ and that our Neurospora image was featured onthe cover of Genetics.

Bob’s arrival at Stanford was warmly celebratedduring a local Neurospora information conference onthe Stanford campus in March 1996. His presence atStanford also brought together Neurospora workers for1-day ‘‘joint lab meetings’’ from the nearby University ofCalifornia campuses of Berkeley and Santa Cruz. Bobespecially enjoyed interactions with students and post-docs and often gave them valuable advice for solvingtheir technical problems. During the 7 years at Stanford,Bob made many friends both in his host departmentand in the medical school. He also taught a biochem-istry course. Lunchtime conversations in the Perkins labwere very lively, with Bob doing most of the talking. Hewas always bubbling with new ideas and hypotheses,which he often tested within the next few weeks. It wasduring his time at Stanford that Bob started to suffer hisown health problems, although this did not affect hisproductivity, as evidenced by his election to the NationalAcademy of Sciences and being awarded the GeneticsSociety of America’s Thomas Hunt Morgan Medal.

In 2003, Bob moved to Northridge mainly to be closeto and help his son’s family. In southern California,he spent some time as a guest in the Departmentof Chemistry and Biochemistry at the University ofCalifornia, Los Angeles, and afterward in the Depart-ment of Biology at California State University at North-ridge. However, he spent most of his work hours in hisconverted home laboratory. Bob’s enthusiasm for re-search was clearly seen in an essay on how to conductresearch after retirement (http://www.genetics-gsa.org/pdf/newsletter_jan07.pdf). He was actively thinking

618 E. U. Selker

about various experiments and writing his final paperjust a couple of weeks before he passed away.

Bob’s energy for work was surpassed only by his ded-ication to others. He was devoted to his family, friends,and colleagues. His years in California were spent asmuch helping others as doing research. Bob’s sacrificeswere legendary, even close to his own end. On learningthat his close friend David Perkins was critically ill atthe end of 2006, Bob, very ill himself, drove with his sonthe 7 hr from Northridge to Palo Alto to see David in thehospital. Although David was heavily sedated and un-responsive, Bob spent more than an hour at David’sside, analyzing the situation and making sure the bestpossible care was being provided. He flew home thenext day, catching pneumonia on the plane, but withthe satisfaction that he was able to do what he could forhis friend.

Eric Selker thanks Joan Bennett, Stan Metzenberg, Mary AnneNelson, Patricia Pukkila, and Matthew Sachs for contributing some ofthe photographs reprinted here. He also thanks Helene Metzenbergand friends and colleagues of Bob Metzenberg who contributedremembrances and he regrets that not all could be included in thisbrief tribute. A more complete collection of pictures and remembrancescan be found at http://pmb.berkeley.edu/�glass/Glasslab_site/Glass_lab_research/bob%20website/bob%20memorial%20webpage.html.Above all, he wants to express his appreciation for Bob, who enrichedhis life and made this article relatively easy to write.

LITERATURE CITED

Aramayo, R., and R. L. Metzenberg, 1996 Meiotic transvection infungi. Cell 86: 103–113.

Butler, D. K., and R. L. Metzenberg, 1989 Premeiotic change ofnucleolus organizer size in Neurospora. Genetics 122: 783–791.

Dolan, P. L., Y. Wu, L. K. Ista, R. L. Metzenberg, M. A. Nelson et al.,2001 Robust and efficient synthetic method for forming DNAmicroarrays. Nucleic Acids Res. 29: E107.

Ferreira, A. V., Z. An, R. L. Metzenberg and N. L. Glass,1998 Characterization of mat A-2, mat A-3 and DmatA mating-type mutants of Neurospora crassa. Genetics 148: 1069–1079.

Freitag, M., P. C. Hickey, N. B. Raju, E. U. Selker and N. D. Read,2004 GFP as a tool to analyze the organization, dynamics andfunction of nuclei and microtubules in Neurospora crassa. FungalGenet. Biol. 41: 897–910.

Glass, N. L., S. J. Vollmer, C. Staben, J. Grotelueschen, R. L.Metzenberg et al., 1988 DNAs of the two mating-type allelesof Neurospora crassa are highly dissimilar. Science 241: 570–573.

Glass, N. L., J. Grotelueschen and R. L. Metzenberg, 1990a Neu-rospora crassa A mating-type region. Proc. Natl. Acad. Sci. USA 87:4912–4916.

Glass, N. L., R. L. Metzenberg and N. B. Raju, 1990b Homothallicsordariaceae from nature: the absence of strains containing onlythe a mating type sequence. Exp. Mycol. 14: 274–289.

Harkness, T. A. A., R. L. Metzenberg, H. Schneider, R. Lill, W.Neupert et al., 1994 Inactivation of the Neurospora crassa geneencoding the mitochondrial protein import receptor MOM19 bythe technique of ‘‘sheltered RIP.’’ Genetics 136: 107–118.

Jacobson, D. J., N. B. Raju and M. Freitag, 2008 Evidence for the ab-sence of meiotic silence in Neurospora tetrasperma. Fungal Genet. Biol.(in press).

Kang, S., and R. L. Metzenberg, 1993 Insertional mutagenesis inNeurospora crassa: cloning and molecular analysis of the preg1gene controlling the activity of the transcriptional activatorNUC-1. Genetics 133: 193–202.

Kelly, W. G., 2006 Standing guard: perinuclear localization of anRNA-dependent RNA polymerase. Proc. Natl. Acad. Sci. USA103: 2007–2008.

Mann, B. J., R. A. Akins, A. M. Lambowitz and R. L. Metzenberg,1988 The structural gene for a phosphorus-repressible phos-phate permease in Neurospora crassa can complement a mutationin positive regulatory gene nuc-1. Mol. Cell. Biol. 8: 1376–1379.

Metzenberg, R. L., 1979 Implications of some genetic controlmechanisms in Neurospora. Microbiol. Rev. 43: 361–383.

Metzenberg, R. L., 1990 The role of similarity and difference infungal mating. Genetics 125: 457–462.

Metzenberg, R. L., 1995 The sexual cycle in Neurospora: from fer-tilization to ascospore discharge, in Biotechnology of Ectomycorrhi-zae, edited by V. Stocchi et al. Plenum Press, New York.

Metzenberg, R. L., 2005 Norman Harold Horowitz, 1915–2005.Genetics 171: 1445–1448.

Metzenberg, R. L., and N. L. Glass, 1990 Mating type and matingstrategies in Neurospora. BioEssays 12: 53–59.

Metzenberg, R. L., J. N. Stevens, E. U. Selker and E. Morzycka-Wroblewska, 1984 A method for finding the genetic map po-sition of cloned DNA fragments. Neurospora Newsl. 31: 35–39.

Metzenberg, R. L., J. N. Stevens, E. U. Selker and E. Morzycka-Wroblewska, 1985 Identification and chromosomal distribu-tion of 5S rRNA genes in Neurospora crassa. Proc. Natl. Acad.Sci. USA 82: 2067–2071.

Nelson, M. A., and R. L. Metzenberg, 1992 Sexual developmentgenes of Neurospora crassa. Genetics 132: 149–162.

Peleg, Y., R. Aramayo, S. Kang, J. G. Hall and R. L. Metzenberg,1996 NUC-2, a component of the phosphate-regulated signaltransduction pathway in Neurospora crassa, is an ankyrin repeatprotein. Mol. Gen. Genet. 252: 709–716.

Perkins, D. D., R. L. Metzenberg, N. B. Raju, E. U. Selker andE. G. Barry, 1986 Reversal of a Neurospora translocation bycrossing over involving displaced rDNA, and methylation ofthe rDNA segments that result from recombination. Genetics114: 791–817.

Randall, T. A., and R. L. Metzenberg, 1995 Species-specific andmating type-specific DNA regions adjacent to mating type idio-morphs in the genus Neurospora. Genetics 141: 119–136.

Raju, N. B., R. L. Metzenberg and P. K. T. Shiu, 2007 Neurosporaspore killers Sk-2 and Sk-3 suppress meiotic silencing by unpairedDNA. Genetics 176: 43–52.

Selker, E. U., C. Yanofsky, K. Driftmier, R. L. Metzenberg,B. Alzner-DeWeerd et al., 1981 Dispersed 5S RNA genes inN. crassa: structure, expression and evolution. Cell 24: 819–828.

Selker, E. U., R. H. Davis and D. D. Perkins, 2005 The 2005Thomas Hunt Morgan Medal: Robert L. Metzenberg. Genetics169: 503–505.

Shiu, P. K., N. B. Raju, D. Zickler and R. L. Metzenberg,2001 Meiotic silencing by unpaired DNA. Cell 107: 905–916.

Shiu, P. K. T., and R. L. Metzenberg, 2002 Meiotic silencing by un-paired DNA: properties, regulation and suppression. Genetics161: 1483–1495.

Shiu, P. K. T., D. Zickler, N. B. Raju, G. Ruprich-Robert and R. L.Metzenberg, 2006 SAD-2 is required for meiotic silencing byunpaired DNA and perinuclear localizataion of SAD-1 RNA-directed RNA polymerase. Proc. Natl. Acad. Sci. USA 103:2243–2248.

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